Engineering monocyte/macrophage−specific glucocerebrosidase expression in human hematopoietic stem cells using genome editing

Samantha G. Scharenberg, Edina Poletto, Katherine L. Lucot, Pasqualina Colella, Adam Sheikali, Thomas J. Montine, Matthew H. Porteus () and Natalia Gomez-Ospina ()
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Samantha G. Scharenberg: Stanford University School of Medicine
Edina Poletto: Gene Therapy Center, Hospital de Clinicas de Porto Alegre
Katherine L. Lucot: Stanford University School of Medicine
Pasqualina Colella: Stanford University School of Medicine
Adam Sheikali: Stanford University School of Medicine
Thomas J. Montine: Stanford University School of Medicine
Matthew H. Porteus: Stanford University School of Medicine
Natalia Gomez-Ospina: Stanford University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Gaucher disease is a lysosomal storage disorder caused by insufficient glucocerebrosidase activity. Its hallmark manifestations are attributed to infiltration and inflammation by macrophages. Current therapies for Gaucher disease include life−long intravenous administration of recombinant glucocerebrosidase and orally-available glucosylceramide synthase inhibitors. An alternative approach is to engineer the patient’s own hematopoietic system to restore glucocerebrosidase expression, thereby replacing the affected cells, and constituting a potential one-time therapy for this disease. Here, we report an efficient CRISPR/Cas9-based approach that targets glucocerebrosidase expression cassettes with a monocyte/macrophage-specific element to the CCR5 safe-harbor locus in human hematopoietic stem and progenitor cells. The targeted cells generate glucocerebrosidase-expressing macrophages and maintain long-term repopulation and multi-lineage differentiation potential with serial transplantation. The combination of a safe-harbor and a lineage-specific promoter establishes a universal correction strategy and circumvents potential toxicity of ectopic glucocerebrosidase in the stem cells. Furthermore, it constitutes an adaptable platform for other lysosomal enzyme deficiencies.

Date: 2020
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DOI: 10.1038/s41467-020-17148-x

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